The working memory functions of the prefrontal cortex (PFC) decline early in the aging process. Working memory depends on recurrent excitation between PFC pyramidal cell microcircuits. With advancing age, there is a loss of pyramidal dendritic spines, thus eroding the anatomical substrate for circuit connectivity. PFC circuits may also be weakened by molecular changes that alter the functional status of network connectivity. NE (norepinephrine) strengthens PFC cognitive function through actions at post-synaptic a2A adrenoceptors (a2A-AR), which inhibit the production of cAMP. cAMP opens HCN (hyperpolarizationactivated cyclic nucleotide gated) channels on PFG dendritic spines, lowering membrane resistance and weakening the efficacy of synaptic inputs. With advancing age, there are fewer a2A-ARs, disinhibited cAMP and increased HCN channels in the PFC. The proposed research tests the hypothesis that excessive cAMP/HCN signaling underlies PFC cognitive deficits early in the aging process, and contributes to eventual spine loss through weakened synaptic connectivity. The research involves 4 Projects and 3 Cores. Project 1 will record from ensembles of PFC neurons in young vs aged monkeys performing working memory tasks to test the hypotheses that PFC networks are weakened with age, and that connectivity can be strengthened by iontophoretic application of agents that inhibit cAMP or block HCN channels. Project 2 will assess molecular changes in the aging rat and monkey PFC that may impact cAMP/HCN signaling and spine loss. This project will also use adenoviral transfection of rat PFC to test whether altered expression of HCN channels and other signaling proteins slow age-related decline in working memory and spine density. Project 3 will record from ensembles of PFC neurons in young and aged rats, and thus observe changes in circuit strength over time in response to viral (Project 2) or pharmacological (Project 4) manipulations. Project 4 will use electron microscopy to visualize changes in NE axons, a2A-AR, and HCN channels in the aging PFC, and will test whether chronic stimulation of a2A-AR with guanfacine will slow working memory impairment and spine loss in aging rats and monkeys. As guanfacine is available for human use, this research can readily translate to treating PFC deficits in the elderly.